Active pharmaceutical ingredients (APIs) that are useful for treating respiratory diseases are often formulated for administration pulmonarily, to wit: by inhalation, such as with portable inhalers. Pulmonary drug delivery methods and compositions that effectively provide the pharmaceutical compound at the specific site of action (the lung) potentially serve to minimize toxic side effects, lower dosing requirements, and decrease therapeutic costs. The development of such systems for pulmonary drug delivery has long been a goal of the pharmaceutical industry.
Inhalation systems commonly used to deliver drugs locally to the pulmonary air passages are dry powder inhalers (DPIs), metered dose inhalers (MDIs), and nebulizers. DPIs generally rely entirely on the patient's inspiratory efforts to introduce a medicament in a dry powder form to the lungs.
To achieve good deposition of aerosolized particles in the lungs, the particles should have an aerodynamic diameter in the respirable size range from 1 to 5 μm. However, fine particles of this size are highly cohesive with poor bulk powder properties (e.g., poor powder flow, fluidization, and dispersibility).
To improve bulk powder properties of dry powder aerosols, micronized drug particles are often blended with coarse lactose monohydrate carrier particles with a geometric diameter between 50 and 200 μm. The blend forms a mixture with the fine particles adhering to the carrier, and the mixture taking on the bulk powder characteristics of the coarse carrier particles.
Engineered particle blends require a delicate balance of surface forces. The adhesive force between the drug and carrier must be strong enough to create an ordered mixture that maintains its structure during filling and on storage, yet weak enough to allow the drug and carrier to separate during aerosol administration. The adhesive force between the fine particles and the carrier particles in current marketed products remains high, however, leading to mean lung delivery efficiencies of just 10-30% of the nominal dose, and mean interpatient variability in lung delivery of approximately 30-50%.
In practice, the engineered blends of micronized drug adhered to lactose carrier particles do not exist as simple ordered mixtures. Drug may be stuck to coarse lactose, to fine lactose, or to itself in large agglomerates. This led some to refer to these complex formulations as “multi-particulate nightmares”. The interactions become even more complex for fixed dose combinations of two or more drugs. Each drug in the combination exhibits a different force of adhesion with the carrier, and a different dependence of drug dispersion from the carrier with flow rate. In addition, there are additional adhesive forces between the two drugs and between each drug and fine particle excipient. The complexity of the interactions can lead to variability in aerosol performance, with differences observed for each drug as a mono-component or in the fixed dose combination, and with differences in dose strength. The complex interactions between the various formulation components leads to difficulty in meeting the “combination rule”, which relates that the in vitro aerosol performance of each drug should be equivalent for the drug alone and in combination. In order to overcome potential issues with meeting the combination rule with lactose blends, some groups have turned to sophisticated devices, where blends of each drug in the fixed dose combination is present in its own receptacle, and the two receptacles are aerosolized concurrently (see for example, Anderson et al., WO 2003/061743).